The use of liposomes as biodegradable delivery systems for a variety of drugs, including their use to direct anthracycline antineoplastic agents to tumor tissue, increase the efficiency of the delivered anthracycline drug and reduce its cardiotoxicity, has been described in the scientific literature with increasing frequency for nearly twenty years. See for example Rahman et al U.S. Pat. No. 3,993,754, issued Nov. 23, 1976; Vanlergerghe et al U.S. Pat. No. 4,217,344, issued Aug. 12, 1980; Papahadjopoul et al U.S. Pat. No. 4,235,871, issued Nov. 25, 1980; Papahadjopoulos et al U.S. Pat. No. 4,241,046, issued Dec. 23, 1980; Apple et al U.S. Pat. No. 4,263,428, issued Apr. 21, 1981 ; Baldeschwieler et al U.S. Pat. No. 4,310,505, issued Jan. 12, 1982; Sakurai et al U.S. Pat. No. 4,330,534, issued May 18, 1982; Morris U.S. Pat. No. 4,331,654, issued May 25, 1982; Kelly U.S. Pat. No. 4,356,167, issued Oct. 26, 1982; Schrank et al U.S. Pat. No. 4,411,894, issued Oct. 25, 1983 ; Rahman et al 4,419,348, issued Dec. 6, 1983; Dingle et al U.S. Pat. No. 4,427,649, issued Jan. 24, 1984; Weder et al U.S. Pat. No. 4,438,052, issued Mar. 20, 1984and Deamer U.S. Pat. No. 4,515,736, issued May 7, 1985. Also, International Application No. PCT/US84/01431, published Mar. 4, 1985 (International Publication No. WO 85/00968) naming Mayhew et al as inventors; International Application No. PCT/US84/00855, published Nov. 21, 1985 (International Publication No. WO 85/05030) naming Janoff et al as inventors; European Patent Application No. 0,004,467, published Oct. 3, 1979 naming Apple et al as inventors; European Patent Application No. 0,036,676, published Sept. 30, 1981 naming Hunt et al as inventors; European Patent Application No. 0,161,445, published Nov. 21, 1985 naming Fukushima et al as inventors; European Patent Application No. 0,198,765, published Oct. 22, 1986 naming Rahman as inventor, and British Patent Application No. GB 2,146,525A, published Apr. 24, 1985 naming Margalit as inventor. Also, Ryman et al, "Possible Use of Liposomes in Drug Delivery", in "Optimization of Drug Delivery, Alfred Benzon Symposium 17" Ed. H. Bundgaard et al (Copenhagen: Munksgaard, 1982); Forssen et al, Proc. Natl. Acad. Sci. USA, 78, No. 3, 1873-1877 (1981); Gabizon et al, Cancer Research, 42, 4734-4739 (1982) and Forssen et al, Cancer Research, 43, 548-550 (1983).
One common drawback associated with prior art methods for preparing liposome drug delivery systems is the low levels of liposome drug entrapment ("trapping efficiency") achievable by such methods. International Patent Applications Nos. PCT/US85/01501 and PCT/USB85/01502, published Feb. 27, 1986 (WO86/01102 and WO6/01103) naming Bally et al as inventors, disclose methods which are reported to provide increases in trapping efficiencies approaching 100% entrapment while, at the same time, increasing the rate at which the drug is loaded into the liposome carrier. These methods involve generating a transmembrane potential creating an ionic gradient for one or more charged species--Na+/K+, Ca++ and H+ are disclosed--across the walls of the liposome. The concentration gradient, as the name implies, results from producing liposomes having different concentrations of charged species within ("the internal phase") and outside of ("the external phase") the vesicles. And see Ostro, Ed. "Liposomes, from Biophysics to Therapeutics" (New York: Marcel Dekker, Inc., 1987), pp. 60-65.
Adding acids, bases or both to control pH while carrying out processes designed to produce small unilamellar liposomes from specified lipid mixtures is disclosed in Hauser. U.S. Pat. No. 4,619,794, issued Oct. 28, 1986. The Hauser patent, however, does not disclose a method of loading drugs into preformed vesicles.